Safety Updates for Biologic Agents Used to Treat Rheumatoid Arthritis

Increasing clinical experience with biologic agents as treatments for rheumatoid arthritis (RA) is yielding increasing data regarding their safety. A number of tumor necrosis factor (TNF) blockers (ie, adalimumab, etanercept, and infliximab) are approved for the treatment of RA. These agents are believed to reduce the inflammatory response thought to contribute to the pathogenesis of RA and, as might be expected, can lead to adverse events associated with immunosuppression. After receiving 240 reports of histoplasmosis in patients receiving TNF inhibitors, the US Food and Drug Administration (FDA) in 2008 sent a notice to clinicians regarding the potential for histoplasmosis and other invasive fungal infections (eg, coccidioidomycosis and blastomycosis) to go unrecognized in patients receiving TNF blockers.¹ Most of the reported histoplasmosis infection cases originated in the Ohio and Mississippi River valleys (ie, areas where Histoplasma capsulatum is endemic). In more than 20 cases, the infection was unrecognized thus treatment was delayed, and the infection proved fatal in 12 cases. The FDA letter urged clinicians to be alert for the possibility of systemic fungal infection in patients from regions of endemic mycoses who are taking TNF blockers and present with symptoms such as fever, malaise, weight loss, sweats, cough, dypsnea, and/or pulmonary infiltrates.

In addition to the FDA warning about TNF blockers, clinicians also recently received safety updates regarding rituximab, a monoclonal antibody directed against CD20 that was approved for the treatment of RA in adults who have had an inadequate response to TNF antagonist therapies.² A case of progressive multifocal leukoencephalopathy (PML) leading to death was reported in a patient with RA who received rituximab. PML was diagnosed 18 months after the patient’s last dose of rituximab and 9 months after the patient received chemotherapy and radiation for the treatment of cancer, preventing any definitive conclusions regarding causality. In addition to RA and cancer, the patient also had a history of Sjögren’s syndrome, undetectable complement C4 levels, and prior treatment with a TNF antagonist and methotrexate. This report represents the first known case of PML in a rituximab-treated patient with RA. These safety warnings stress the need for clinicians to be alert for possible side effects caused by the immunosuppressive actions of the biologic agents approved for the treatment of RA.

Practice Points

• In regions of endemic mycoses, clinicians should be alert to the possibility of invasive fungal infections, such as histoplasmosis, in patients receiving TNF blockers
• Diagnosis of PML should be considered in any patient treated with rituximab who presents with new-onset neurologic manifestations

References

1. US Food and Drug Administration. Information for healthcare professionals Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab). Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/TNF_blockersHCP.htm. Accessed November 11, 2008.
2. Genentech I. "Dear Doctor" letter. Available at: http://www.gene.com/gene/products/information/pdf/rituxan_dhcp_letter_0908.pdf. Accessed December 15, 2008.